ANS / lec. 13Sep 14, 2012 · Pharma Sheet Dr.Muneer 4 Organ System Effects of Ganglionic Blockers • Central Nervous System: – Mecamylamine, crosses the blood-brain barrier and

Pharma Sheet Dr.Muneer

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ANS / lec. 13

Bara’a Rawashdeh

Munir Gharaibeh

21/11/2012


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Note: no need to refer to the slides ^_^

Chemistry & Pharmacokinetics:

• Tetraethylammonium (TEA)

– The first to be recognized as having this action, has a very short

duration of action.

• Hexamethonium:

– The first drug effective for management of hypertension.

• Decamethonium:

– The "C10" analog of hexamethonium, is a depolarizing

neuromuscular blocking agent.

• Mecamylamine:

– A secondary amine, was developed to improve absorption from the

gastrointestinal tract because the quaternary amine ganglion-

blocking compounds were poorly and erratically absorbed after oral

administration.


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• Trimethaphan A short-acting ganglion blocker, is inactive orally and is given

by intravenous infusion.

**Mechanism of Action:

• Ganglionic nicotinic receptors, like those of the skeletal muscle

neuromuscular junction, are subject to both depolarizing and

nondepolarizing blockade

• Nicotine itself and even acetylcholine (if amplified with a cholinesterase

inhibitor) can produce depolarizing ganglion block.

• Drugs now used as ganglion blockers are classified as nondepolarizing

competitive antagonists.

• However, hexamethonium actually produces most of its blockade by

occupying sites in or on the nicotinic ion channel, not by occupying the

cholinoceptor itself.

In contrast, trimethaphan appears to block the nicotinic receptor, not the channel

pore. Blockade can be surmounted by increasing the concentration of an agonist,

e.g. acetylcholine.


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Organ System Effects of Ganglionic Blockers

• Central Nervous System:

– Mecamylamine, crosses the blood-brain barrier and readily enters

the CNS. Sedation, tremor, choreiform movements, and mental

aberrations have been reported as effects of mecamylamine.

• Eye:

– Cycloplegia with loss of accommodation. Ganglionic blockade often

causes moderate dilation of the pupil because parasympathetic tone

usually dominates this tissue.

• Cardiovascular System:

– Ganglionic blockade causes a marked decrease in arteriolar and

venomotor tone. The blood pressure may fall precipitously because

both peripheral vascular resistance and venous return are decreased.

– Hypotension is especially marked in the upright position (orthostatic

or postural hypotension).

– Cardiac effects include diminished contractility and, because the

sinoatrial node is usually dominated by the parasympathetic nervous

system, a moderate tachycardia.

• Gastrointestinal Tract

– Secretion is reduced, Motility is profoundly inhibited, and

constipation can be marked.

• Other Systems

– Ganglionic blockade causes hesitancy in urination and may

precipitate urinary retention in men with prostatic hyperplasia.


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Sexual function is impaired in that both erection and ejaculation may

be prevented by moderate doses.

– Sweating is reduced by the ganglion-blocking drugs.

Response to Autonomic Drugs:

– Patients receiving ganglion-blocking drugs are fully responsive to

autonomic drugs acting on muscarinic, alpha , and beta adrenergic

receptors because these effector cell receptors are not blocked.

– In fact, responses may be exaggerated or even reversed e.g.

intravenously administered norepinephrine may cause tachycardia

rather than bradycardia), because homeostatic reflexes, which

normally moderate autonomic responses, are absent.

Clinical Applications & Toxicity of Ganglionic Blockers

• Ganglion blockers are used infrequently because more selective autonomic

blocking agents are available.

• Mecamylamine

– blocks central nicotinic receptors and has been advocated as a

possible adjunct with the transdermal nicotine patch to reduce

nicotine craving in patients attempting to quit smoking.

• Trimethaphan

– is occasionally used in the treatment of hypertensive emergencies

and dissecting aortic aneurysm; in producing hypotension, which can

be of value in neurosurgery to reduce bleeding in the operative field.

• The toxicity of the ganglion-blocking drugs is widespread because of

involvement of all the autonomic nervous system.


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• For most patients, these effects are intolerable except for acute use.

Sympathomimetics or Adrenergic Drugs:

These are the drugs which produce effects similar to the effects produced

by endogenously released adrenergic neurotransmitters.

These drugs can work at adrenergic receptors, as well as other sites of the

adrenergic neuron and can affect various steps of the life cycle of the

neurotransmitter.

Life Cycle of Norepinephrine:


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Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent

carrier (A).

Tyrosine is converted to dopamine , and transported into the vesicle by the vesicular

monoamine transporter (VMAT), which can be blocked by reserpine .The same carrier

transports NE and several other amines into these granules.

Dopamine is converted to NE in the vesicle by dopamine - - hydroxylase.

Physiologic release of transmitter occurs when an action potential opens voltage-

sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with

the surface membrane results in expulsion of norepinephrine, cotransmitters, and

dopamine - - hydroxylase.

Release can be blocked by drugs such as guanethidine and bretylium.

After release, norepinephrine diffuses out of the cleft or is transported into the

cytoplasm of the terminal by the norepinephrine transporter (NET), which can be

blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional

cells.

Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-

associated proteins; VAMPs, vesicle-associated membrane proteins.

Biosynthesis of Catecholamines:


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Metabolism of Catecholamines:


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Autonomic and hormonal control of cardiovascular function:

Two feedback loops are present: the autonomic nervous system loop and the hormonal

loop.

The sympathetic nervous system directly influences four major variables: peripheral

vascular resistance, heart rate, force, and venous tone. It also directly modulates renin

production.

The parasympathetic nervous system directly influences heart rate.

Angiotensin II stimulates aldosterone secretion, and directly increases peripheral

vascular resistance and facilitates sympathetic effects

The net feedback effect of each loop is to compensate for changes in arterial blood

pressure.

Thus, decreased blood pressure due to blood loss would evoke increased sympathetic

outflow and renin release.

Conversely, elevated pressure due to the administration of a vasoconstrictor drug

would cause reduced sympathetic outflow, reduced renin release, and increased

parasympathetic (vagal) outflow.


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Alpha1 receptors are coupled via G proteins in the Gq family to phospholipase C

leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol

(DAG)

* Alpha2 receptors inhibit adenylyl cyclase and decrease cAMP.

* Beta Receptors stimulates adenylyl cyclase and increase cAMP.


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Dopamine Receptors:

The D1 receptor is typically associated with the stimulation of adenylyl cyclase

for example, D1-receptor-induced smooth muscle relaxation is presumably due

to cAMP accumulation in the smooth muscle of those vascular beds in which

dopamine is a vasodilator.

D2 receptors have been found to inhibit adenylyl cyclase activity, open

potassium channels, and decrease calcium influx.

Adrenergic Receptors


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Dopamine Receptors


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Dopamine Receptor Subtypes


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Catecholamines


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Noncatecholamines

Structure Activity Relationships

Substitution on the Benzene Ring

Substitution on the Amino Group

Substitution on the Alpha Carbon

Substitution on the Benzene Ring :

◦ Maximal α and β activity is found with catecholamines, i.e. drugs having –

OH groups at the 3 and 4 positions on the benzene ring.


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◦ The absence of one or the other of these groups, particularly the hydroxyl

at C3, without other substitutions on the ring may dramatically reduce the

potency of the drug. For example, phenylephrine is much less potent than

epinephrine; indeed, α –receptor affinity is decreased about 100-fold and

β activity is almost negligible .

No –OH groups on the ring means:

1-COMT is not effective, so the drug is effective orally.

2- Lipid solubility increases, so the drug has a CNS effect. For example, ephedrine and

amphetamine are orally active, have a prolonged duration of action, and produce

central nervous system effects not typically observed with the catecholamines.

Substitution on the Amino Group:

◦ Increasing the size of alkyl substituents on the amino group tends to

increase β –receptor activity. For example, methyl substitution on

norepinephrine, yielding epinephrine, enhances activity at β 2 receptors.

◦ Beta activity is further enhanced with isopropyl substitution at the amino

nitrogen (isoproterenol).

◦ Beta2-selective agonists generally require a large amino substituent

group. The larger the substituent on the amino group, the lower the

activity at α receptors; for example, isoproterenol is very weak at α

receptors.

Substitution on the Alpha Carbon

◦ Substitutions at the α carbon, block oxidation by monoamine oxidase

(MAO) and prolong the action of such drugs, particularly the

noncatecholamines.

◦ Ephedrine and amphetamine are examples of - α carbon substituted

compounds .

Done By: Bara’a Rawashdeh

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ANS / lec. 13Sep 14, 2012 · Pharma Sheet Dr.Muneer 4 Organ System Effects of Ganglionic Blockers • Central Nervous System: – Mecamylamine, crosses the blood-brain barrier and